4.7 Article

MitoNEET prevents iron overload-induced insulin resistance in H9c2 cells through regulation of mitochondrial iron

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JOURNAL OF CELLULAR PHYSIOLOGY
卷 -, 期 -, 页码 -

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WILEY
DOI: 10.1002/jcp.31044

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insulin resistance; iron overload; Mitochondria; MitoNEET; reactive oxygen species

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Iron overload leads to insulin resistance in H9c2 cardiomyoblast cells. Overexpression of MitoNEET can protect against iron accumulation in the mitochondria and subsequent insulin resistance. Iron overload increases mitochondrial iron content, ROS production, mitochondrial fission, and decreases insulin-stimulated Akt and ERK1/2 phosphorylation. MitoNEET overexpression attenuates these effects and upregulates levels of PGC1 alpha protein.
Iron overload (IO) induces insulin resistance in H9c2 cardiomyoblast cells. Here, we used H9c2 cells overexpressing MitoNEET to examine the potential for protection against iron accumulation in the mitochondria and subsequent insulin resistance. In control H9c2 cells, IO was observed to increase mitochondrial iron content, reactive oxygen species (ROS) production, mitochondrial fission, and reduced insulin-stimulated Akt and ERK1/2 phosphorylation. IO did not significantly affect mitophagy, or mitochondrial content, however, an increase in peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha) protein expression, a key regulator of mitochondrial biogenesis, was observed. MitoNEET overexpression was able to attenuate the effects of IO on mitochondrial iron content, reactive oxygen species, mitochondrial fission, and insulin signaling. MitoNEET overexpression also upregulated levels of PGC1 alpha protein. The mitochondria-targeted antioxidant, Skq1, prevented IO-induced ROS production and insulin resistance in control cells, indicating mitochondrial ROS plays a causal role in the onset of insulin resistance. The selective mitochondrial fission inhibitor, Mdivi-1, prevented IO-induced mitochondrial fission, however, it did not alleviate IO-induced insulin resistance. Collectively, IO causes insulin resistance in H9c2 cardiomyoblasts and this can be averted by reduction of mitochondrial iron accumulation and ROS production by overexpression of the MitoNEET protein.

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